Novel dual brain-targeting lipid material and application thereof in drug delivery system

A lipid material and brain-targeting technology, applied in the field of medicine, can solve the problems of limited targeting ability and limited improvement

Inactive Publication Date: 2018-09-11
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Although glucose or vitamin C single-modified liposomes can improve the brain targeting of paclitaxel liposomes to a certain extent and promote the accumulation of drugs in the central nervous system, this improvement is still very limited, and the relative uptake in the brain Compared with the original drug, the ratio Re and peak concentration ratio Ce are only 2~4 times
This may be due to the limited targeting ability due to the modification of a single targeting molecule; There is a saturation of the transporter, which will cause the drug to be unable to penetrate the brain barrier and reach the brain

Method used

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  • Novel dual brain-targeting lipid material and application thereof in drug delivery system
  • Novel dual brain-targeting lipid material and application thereof in drug delivery system
  • Novel dual brain-targeting lipid material and application thereof in drug delivery system

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Preparation of Compound 2

[0042]

[0043] Add succinic anhydride 1 (5.00 g, 49.96 mmol), benzyl alcohol (5.94 g, 54.96 mmol) and 4-dimethylaminopyridine (DMAP, 61 mg, 0.50 mmol) into 50 mL of tetrahydrofuran, heat up to 50 °C The reaction was stirred for 5 hours. Remove the solvent under reduced pressure, add 100 mL of ethyl acetate to the residue, wash with saturated sodium bicarbonate (100 mL), discard the organic layer, adjust the aqueous layer to pH = 2 with dilute hydrochloric acid (1 mol / L), and filter , the filter cake was dried to obtain 6.58 g of white solid, yield 63.29%, Mp:60-62 o c.

Embodiment 2

[0045] Preparation of Compound 4

[0046]

[0047] Anhydrous glucose 3 (Glu, 18.02 g, 0.10 mol) was dissolved in 230 mL of anhydrous pyridine, and after cooling in an ice bath for 5 minutes, trimethylchlorosilane (TMSCl, 76.06 mL, 0.60 mol) and hexamethyl A mixed solution of disilazyl amine (HDMS, 62.88 mL, 0.30 mol) was slowly added dropwise to the above pyridine solution, and stirred at room temperature for 24 hours. Remove the solvent under reduced pressure, add 200 mL of water to disperse, extract the aqueous layer with diethyl ether (200 mL × 2), combine the organic layers, and successively wash with dilute hydrochloric acid (1 mol / L, 200 mL × 2), saturated aqueous sodium chloride (200 mL × 2) Wash, dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain 52.87 g of yellow oil, with a yield of 97.70%. The product can be directly subjected to the next reaction without purification.

Embodiment 3

[0049] Preparation of compound 5

[0050]

[0051] Compound 4 (10.99 g, 20.31 mmol) was dissolved in a mixed solution of acetone and methanol (5:8, 65 mL), and acetic acid (2.1 mL, 36.72 mmol) in acetone and methanol (5:8) was slowly added dropwise under ice cooling. 8, 6.5 mL) mixed solution. After the dropwise addition, the reaction solution was moved to room temperature and stirred for 2 hours, and sodium carbonate powder (3.30 g, 31.14 mmol) was added to continue stirring at room temperature for 20 minutes. The white solid was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=50 / 1) to obtain 7.40 g of a colorless oil with a yield of 77.65%. 1 H NMR (400 MHz, CDCl 3 , ppm) δ : 0.12-0.18 (m, 36 H), 3.31-0.34 (m, 1 H), 3.37 (dd, 1 H, J = 2.8 Hz, 9.2 Hz), 3.55(t, 1 H, J = 8.8 Hz), 3.62-3.64 (m, 3H), 3.79 (t, 1 H, J = 8.8 Hz), 5.02 (d,1 H, J =...

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Abstract

The invention discloses a novel lipid material which is used for prolonging the circulation time and increasing drug targets to be transmitted to the brain. According to the novel lipid material, polyethylene glycol is used for bridging, one side of polyethylene glycol is connected with cholesterol, and the other side of polyethylene glycol is connected with glucose and vitamin C, so that the defect of the targeting capability of lipidosomes modified by single glucose or vitamin C is made up for, transfer for crossing a blood-brain and blood-brain spinal fluid dual barrier is achieved, the brain targeting of drugs is improved, and the central concentration of the drugs is increased. The novel lipid material can be used for different dosage forms including liposomes, nanoparticles and micelles, and paclitaxel liposomes prepared from the material have an obvious brain targeting function and wide application prospects.

Description

technical field [0001] The present invention relates to a new type of lipid material and its application in drug delivery system, which has the functions of prolonging the circulation in the body and dual brain-targeted drug delivery, including the preparation of the material and its use as a drug carrier in drug delivery The application belongs to the technical field of medicine. Background technique [0002] According to statistics, about 1 / 5 of the world's population suffers from various types and degrees of central nervous system (CNS) diseases, including brain tumors, acute or chronic pain syndrome, epilepsy, encephalitis, cerebral ischemia and neurodegeneration Diseases (e.g. Alzheimer's, Parkinson's, etc.). As the world's population ages, this trend will intensify and have serious implications for human health. Brain barrier is the general term for blood-brain barrier, blood-cerebrospinal fluid barrier and cerebrospinal fluid-brain barrier. While the central nervou...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G65/336A61K47/22A61K47/26A61K9/127A61K31/337A61P35/00
CPCA61K9/1271A61K31/337A61K47/22A61K47/26A61P35/00C08G65/336
Inventor 吴勇海俐郭丽赵毅张力肖文娇彭瑶
Owner SICHUAN UNIV
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